U.S. patent application number 10/182638 was filed with the patent office on 2003-07-24 for novel 1,3-dihydro-2h-indol-2-one derivatives, preparation method and pharmaceutical composition containing them.
Invention is credited to Schoentjes, Bruno, Serradeil-Le Gal, Claudine, Wagnon, Jean.
Application Number | 20030139413 10/182638 |
Document ID | / |
Family ID | 8846308 |
Filed Date | 2003-07-24 |
United States Patent
Application |
20030139413 |
Kind Code |
A1 |
Schoentjes, Bruno ; et
al. |
July 24, 2003 |
NOVEL 1,3-DIHYDRO-2H-INDOL-2-ONE DERIVATIVES, PREPARATION METHOD
AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
Abstract
The invention relates to compounds of formula: 1 and their
solvates and/or hydrates exhibiting affinity for the
arginine-vasopressin V.sub.1b receptors or for both V.sub.1b and
V.sub.1a receptors. The invention also relates to their process of
preparation, to the intermediate compounds of formula (II) of use
for their preparation, to the pharmaceutical compositions
comprising them and to their use for the preparation of
medicaments.
Inventors: |
Schoentjes, Bruno;
(Strasbourg, FR) ; Serradeil-Le Gal, Claudine;
(Escalquens, FR) ; Wagnon, Jean; (Montpellier,
FR) |
Correspondence
Address: |
SANOFI-SYNTHELABO INC.
9 GREAT VALLEY PARKWAY
P.O. BOX 3026
MALVERN
PA
19355
US
|
Family ID: |
8846308 |
Appl. No.: |
10/182638 |
Filed: |
November 25, 2002 |
PCT Filed: |
January 24, 2001 |
PCT NO: |
PCT/FR01/00228 |
Current U.S.
Class: |
514/233.5 ;
544/143 |
Current CPC
Class: |
A61P 17/06 20180101;
A61P 27/06 20180101; A61P 15/08 20180101; A61P 25/06 20180101; A61P
1/04 20180101; A61P 9/04 20180101; A61P 9/10 20180101; A61P 3/06
20180101; A61P 25/24 20180101; A61P 37/04 20180101; A61P 43/00
20180101; A61P 3/10 20180101; A61P 25/28 20180101; A61P 29/00
20180101; C07D 413/04 20130101; A61P 25/14 20180101; A61P 9/12
20180101; A61P 25/22 20180101; A61P 9/00 20180101; A61P 13/12
20180101; A61P 3/04 20180101; A61P 5/00 20180101; A61P 11/00
20180101; A61P 1/00 20180101; A61P 25/00 20180101; A61P 1/08
20180101; A61P 11/06 20180101; A61P 19/02 20180101; A61P 1/16
20180101; A61P 35/00 20180101; A61P 25/16 20180101; A61P 27/12
20180101 |
Class at
Publication: |
514/233.5 ;
544/143 |
International
Class: |
A61K 031/5377; C07D
413/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 25, 2000 |
FR |
00 00958 |
Claims
1. A compound of formula: 15in which: R.sub.1 represents a halogen
atom; a (C.sub.1-C.sub.4)alkyl; a (C.sub.1-C.sub.4)alkoxy; a
trifluoromethyl radical; or a trifluoromethoxy radical; R.sub.2
represents a hydrogen atom; a halogen atom; a
(C.sub.1-C.sub.4)alkyl; a (C.sub.1-C.sub.4)alkoxy- ; or a
trifluoromethyl radical; or else R.sub.2 is in the 6-position of
the indol-2-one ring and R.sub.1 and R.sub.2 together represent the
bivalent trimethylene radical; R.sub.3 represents a halogen atom; a
hydroxyl; a (C.sub.1-C.sub.2)alkyl; a (C.sub.1-C.sub.2)alkoxy; or a
trifluoromethoxy radical; R.sub.4 represents a hydrogen atom; a
halogen atom; a (C.sub.1-C.sub.2)alkyl; or a
(C.sub.1-C.sub.2)alkoxy; or else R.sub.4 is in the 3-position of
the phenyl and R.sub.3 and R.sub.4 together represent the
methylenedioxy radical; R.sub.5 represents an ethylamino group; a
dimethylamino group; an azetidin-1-yl radical; or a
(C.sub.1-C.sub.2) alkoxy; R.sub.6 represents a
(C.sub.1-C.sub.4)alkoxy; R.sub.7 represents a
(C.sub.1-C.sub.4)alkoxy; the carbon atom bearing the COR.sub.5
substituent in the (S) configuration and its solvates and/or
hydrates.
2. The compound as claimed in claim 1, in the form of optically
pure isomers, the carbon atom in the 3-position of the indol-2-one
has either the (R) configuration or the (S) configuration.
3. The compound as claimed in claim 2, in the form of a
levorotatory isomer.
4. A
(3S)-4-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl-
)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylmorpholine-3-carboxamide,
levorotatory isomer, its solvates and/or its hydrates.
5. A
(3S)-4-[6-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl-
)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-morpholine-3-carb-
oxamide, levorotatory isomer, its solvates and/or its hydrates.
6. A
(3S)-4-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl-
)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-morpholine-3-carb-
oxamide, levorotatory isomer, its solvates and/or its hydrates.
7. A process for the preparation of the compounds of formula (I) as
claimed in claim 1, their solvates and/or their hydrates,
characterized in that: a compound of formula: 16in which R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined for a compound
of formula (I) in claim 1, is reacted, in the presence of a base,
with a halide of formula: 17in which R.sub.6 and R.sub.7 are as
defined for a compound of formula (I) in claim 1 and Hal represents
a halogen atom.
8. A compound of formula: 18in which: R.sub.1 represents a halogen
atom; a (C.sub.1-C.sub.4)alkyl; a (C.sub.1-C.sub.4)alkoxy; a
trifluoromethyl radical; or a trifluoromethoxy radical; R.sub.2
represents a hydrogen atom; a halogen atom; a
(C.sub.1-C.sub.4)alkyl; a (C.sub.1-C.sub.4)alkoxy- ; or a
trifluoromethyl radical; or else R.sub.2 is in the 6-position of
the indol-2-one ring and R.sub.1 and R.sub.2 together represent the
bivalent trimethylene radical; R.sub.3 represents a halogen atom; a
hydroxyl; a (C.sub.1-C.sub.2)alkyl; a (C.sub.1-C.sub.2)alkoxy; or a
trifluoromethoxy radical; R.sub.4 represents a hydrogen atom; a
halogen atom; a (C.sub.1-C.sub.2)alkyl; or a
(C.sub.1-C.sub.2)alkoxy; or else R.sub.4 is in the 3-position of
the phenyl and R.sub.3 and R.sub.4 together represent the
methylenedioxy radical; R.sub.5 represents an ethylamino group; a
dimethylamino group; an azetidin-1-yl radical; or a
(C.sub.1-C.sub.2) alkoxy; and their salts with inorganic or organic
acids, in the form of optically pure isomer or in the form of a
mixture of diastereoisomers.
9. A pharmaceutical composition comprising, as active ingredient, a
compound as claimed in any one of claims 1 to 6, one of its
pharmaceutically acceptable solvates and/or hydrates.
10. The use of a compound as claimed in any one of claims 1 to 6,
its pharmaceutically acceptable solvates and/or hydrates, for the
preparation of medicaments intended for the treatment of any
pathology where arginine-vasopressin and/or its V.sub.1b receptors
or both its V.sub.1b receptors and its V.sub.1a receptors are
implicated.
11. A medicament characterized in that it is composed of a compound
as claimed in any one of claims 1 to 6.
Description
[0001] A subject of the present invention is novel
1,3-dihydro-2H-indol-2-- one derivatives, a process for their
preparation and the pharmaceutical compositions comprising
them.
[0002] The compounds according to the present invention exhibit an
affinity and a selectivity for arginine-vasopressin (AVP) V.sub.1b
receptors or for both V.sub.1b and V.sub.1a receptors.
[0003] AVP is a hormone known for its antidiuretic effect and its
effect in regulating arterial pressure. It stimulates several types
of receptors: V.sub.1 (V.sub.1a, V.sub.1b) or V.sub.2. These
receptors are located in particular in the liver, vessels
(coronary, renal, cerebral), platelets, kidney, uterus, adrenal
glands, pancreas, central nervous system or pituitary gland. AVP
thus exerts cardiovascular, hepatic, pancreatic, antidiuretic and
platelet-aggregating effects and effects on the central and
peripheral nervous system and on the uterine sphere.
[0004] The localization of various receptors is described in: S.
Jard et al., Vasopressin and oxytocin receptors: an overview, in
Progress in Endocrinology, H. Imura and K. Shizurne ed., Experta
Medica, Amsterdam, 1988, 1183-1188, and in the following articles:
J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev.,
1991, 43 (1), 73-108.
[0005] More particularly, AVP V.sub.1a receptors are located in
numerous peripheral organs and in the brain. They have been cloned
in the rat and man and they regulate the majority of known effects
of AVP: platelet aggregation; uterine contractions; vessel
contraction; the secretion of aldosterone, of cortisol, of CRF
(corticotropin-releasing factor) and of adrenocorticotrophic
hormone (ACTH); hepatic glycogenolysis, cell proliferation and the
main central effects of AVP (hypothermia, memory, and the
like).
[0006] The V.sub.1b receptors were initially identified in the
adenohypophysis of various animal species (rat, pig, cow, sheep,
and the like), including in man (S. Jard et al., Mol. Pharmacol.,
1986, 30, 171-177; Y. Arsenijevic et al., J. Endocrinol., 1994,
141, 383-391; J. Schwartz et al., Endocrinology, 1991, 129 (2),
1107-1109; Y. de Keyser et al., FEBS Letters, 1994, 356, 215-220),
where they stimulate the release of adrenocorticotrophic hormone by
AVP and potentiate the effects of CRF on the release of ACTH (G. E.
Gillies et al., Nature, 1982, 299, 355). In the hypothalamus, the
V.sub.1b receptors also induce a direct release of CRF
(Neuroendocrinology, 1994, 60, 503-508) and are, in these various
respects, implicated in stress situations.
[0007] These V.sub.1b receptors have been cloned in the rat, man
and mouse (Y. de Keyser, FEBS Letters, 1994, 356, 215-220; T.
Sugimoto et al., J. Biol. Chem., 1994, 269 (43), 27088-27092; M.
Saito et al., Biochem. Biophys. Res. Commun., 1995, 212 (3),
751-757; S. J. Lolait et al., Neurobiology, 1996, 92, 6783-6787; M.
A. Ventura et al., Journal of Molecular Endocrinology, 1999, 22,
251-260) and various studies (in situ hybridization, PCR
(Polymerase Chain Reaction), and the like) reveal ubiquitous
localization of these receptors in various central tissues (brain,
hypothalamus and adenohypophysis, in particular) and peripheral
tissues (kidney, pancreas, adrenal glands, heart, lungs, intestine,
stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina,
thyroid, and the like) and in some tumors (hypophyseal or pulmonary
tumors, and the like), suggesting a broad biological and/or
pathological role of these receptors and potential involvement in
various diseases.
[0008] By way of examples, in the rat, studies have shown that AVP,
via the V.sub.1b receptors, regulates the endocrine pancreas,
stimulating the secretion of insulin and of glucagon (B. Lee et
al., Am. J. Physiol., 269 (Endocrinol. Metab. 32), E1095-E1100,
1995) or the production of catecholamines in the medulloadrenal,
which is the site of a local synthesis of AVP (E. Grazzini et al.,
Endocrinology, 1996, 137 (a), 3906-3914). Thus, in the last tissue,
AVP, via these receptors, would have a crucial role in some types
of adrenal pheochromocytomas which secrete AVP and which, for this
reason, bring about a sustained production of catecholamines which
are the cause of hypertensions which are resistant to
angiotensin-II receptor antagonists and to converting enzyme
inhibitors. The adrenal cortex is also rich in V.sub.1a receptors
involved in the production of gluco- and mineralocorticoids
(aldosterone and cortisol). Via these receptors, AVP (circulating
or synthesized locally) can bring about production of aldosterone
with an effectiveness comparable to that of angiotensin II (G.
Guillon et al., Endocrinology, 1995, 136 (3), 1285-1295). Cortisol
is a powerful regulator of the production of ACTH, the stress
hormone.
[0009] Recent studies have also shown that the adrenal glands are
capable of directly releasing CRF and/or ACTH via the activation of
the V.sub.1b and/or V.sub.1a receptors carried by the cells of the
medulla (G. Mazzocchi et al., Peptides, 1997, 18(2), 191-195; E.
Grazzini et al., J. Clin. Endocrinol. Metab., 1999, 84 (6),
2195-2203).
[0010] The V.sub.1b receptors are also regarded as a label for
ACTH-secreting tumors, which are some pituitary tumors and some
bronchial (Small Cell Lung Cancers or SCLC), pancreatic, adrenal
and thyroid carcinomas, resulting in some cases in Cushing's
syndrome (J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173;
G. A. Wittert et al., Lancet, 1990, 335, 991-994; G. Dickstein et
al., J. Clin. Endocrinol. Metab., 1996, 81 (8), 2934-2941). The
V.sub.1a receptors are, for their part, a more specific label for
small cell lung cancers (SCLC) (P. J. Woll et al., Biochem.
Biophys. Res. Commun., 1989, 164 (1), 66-73). Thus, the compounds
according to the present invention are obvious diagnostic tools and
offer a novel therapeutic approach in the proliferation and
detection of these tumors, at an early stage too (radiolabeling;
SPECT (Single Photon Emission Computed Tomography); PET Scan
(Positron Emission Tomography Scanner)).
[0011] The lavish presence of the messenger of the V.sub.1b
receptors in the stomach and intestine suggests involvement of AVP
via this receptor in the release of gastrointestinal hormones, such
as cholecystokinin, gastrin or secretin (T. Sugimoto et al.,
Molecular cloning and functional expression of V.sub.1b receptor
gene, in Neurohypophysis: Recent Progress of Vasopressin and
Oxytocin Research; T. Saito, K. Kurokawa and S. Yoshida ed.,
Elvesier Science, 1995, 409-413).
[0012] 1,3-Dihydro-2H-indol-2-one derivatives have been disclosed
in some patent applications as ligands of the arginine-vasopressin
and/or oxytocin receptors: mention may be made of patent
applications WO 93/15051, EP 636 608, EP 636 609, WO 95/18105, WO
97/15556 and WO 98/25901.
[0013] To date, no nonpeptide compound having an affinity and a
selectivity for arginine-vasopressin V.sub.1b receptors or for both
V.sub.1b and V.sub.1a receptors is known.
[0014] Novel 1,3-dihydro-2H-indol-2-one derivatives have now been
found which exhibit an affinity and a selectivity for
arginine-vasopressin V.sub.1b receptors or for both V.sub.1b and
V.sub.1a receptors.
[0015] These compounds can be used for the preparation of
medicaments of use in the treatment or prevention of any pathology
where arginine-vasopressin and/or the V.sub.1b receptors or both
the V.sub.1b receptors and the V.sub.1a receptors are implicated,
in particular in the treatment or prevention of conditions of the
cardiovascular system, for example hypertension of the central
nervous system, for example stress, anxiety, depression,
obsessive-compulsive disorder or panic attacks of the renal system
or of the gastric system and in the treatment of small cell lung
cancers, of obesity of type-II diabetes of insulin resistance of
hypertriglyceridemia of atherosclerosis of Cushing's syndrome; or
of any pathology resulting from stress and chronic stress
conditions.
[0016] Thus, according to one of its aspects, the subject of the
present invention is compounds of formula: 2
[0017] in which:
[0018] R.sub.1 represents a halogen atom; a (C.sub.1-C.sub.4)alkyl;
a (C.sub.1-C.sub.4)alkoxy; a trifluoromethyl radical; or a
trifluoromethoxy radical;
[0019] R.sub.2 represents a hydrogen atom; a halogen atom; a
(C.sub.1-C.sub.4)alkyl; a (C.sub.1-C.sub.4)alkoxy; or a
trifluoromethyl radical;
[0020] or else R.sub.2 is in the 6-position of the indol-2-one ring
and R.sub.1 and R.sub.2 together represent the bivalent
trimethylene radical;
[0021] R.sub.3 represents a halogen atom; a hydroxyl; a
(C.sub.1-C.sub.2)alkyl; a (C.sub.1-C.sub.2)alkoxy; or a
trifluoromethoxy radical;
[0022] R.sub.4 represents a hydrogen atom; a halogen atom; a
(C.sub.1-C.sub.2)alkyl; or a (C.sub.1-C.sub.2)alkoxy;
[0023] or else R.sub.4 is in the 3-position of the phenyl and
R.sub.3 and R.sub.4 together represent the methylenedioxy
radical;
[0024] R.sub.5 represents an ethylamino group; a dimethylamino
group; an azetidin-1-yl radical; or a (C.sub.1-C.sub.2)alkoxy;
[0025] R.sub.6 represents a (C.sub.1-C.sub.4)alkoxy;
[0026] R.sub.7 represents a (C.sub.1-C.sub.4)alkoxy; and their
solvates and/or hydrates.
[0027] The term "halogen atom" is understood to mean a chlorine,
bromine, fluorine or iodine atom.
[0028] The term "alkyl" or the term "alkoxy" are respectively
understood to mean a linear or branched alkyl or alkoxy radical
respectively.
[0029] The compounds of formula (I) comprise at least 2 asymmetric
carbon atoms, the carbon atom being the COR.sub.5 substituent in
the (S) configuration. The optically pure isomers of the compounds
of formula (I) and their mixtures in any proportion form part of
the invention.
[0030] According to the present invention, preference is given to
the compounds of formula (I) in which:
[0031] R.sub.1 represents a halogen atom; a (C.sub.1-C.sub.4)alkyl;
a trifluoromethyl radical; or a trifluoromethoxy radical;
[0032] R.sub.2 represents a hydrogen atom; a halogen atom; a
(C.sub.1-C.sub.4)alkyl; a (C.sub.1-C.sub.4)alkoxy; or a
trifluoromethyl radical;
[0033] or else R.sub.2 is in the 6-position of the indol-2-one ring
and R.sub.1 and R.sub.2 together represent the bivalent
trimethylene radical;
[0034] R.sub.3 represents a halogen atom; a hydroxyl; or a
(C.sub.1-C.sub.2) alkoxy;
[0035] R.sub.4 represents a hydrogen atom; a halogen atom; a
(C.sub.1-C.sub.2)alkyl; or a (C.sub.1-C.sub.2)alkoxy;
[0036] or else R.sub.4 is in the 3-position of the phenyl and
R.sub.3 and R.sub.4 together represent the methylenedioxy
radical;
[0037] R.sub.5 represents an ethylamino group; a dimethylamino
group; an azetidin-1-yl radical; or a (C.sub.1-C.sub.2) alkoxy;
[0038] R.sub.6 represents a (C.sub.1-C.sub.4)alkoxy;
[0039] R.sub.7 represents a (C.sub.1-C.sub.4)alkoxy;
[0040] and their solvates and/or hydrates.
[0041] According to the present invention, preference is given to
the compounds of formula (I) in which R.sub.1 represents a chlorine
atom, a methyl radical or a trifluoromethoxy radical.
[0042] According to the present invention, preference is given to
the compounds of formula (I) in which R.sub.2 represents a hydrogen
atom or is in the 6-position of the indol-2-one and represents a
chlorine atom, a methyl radical, a methoxy radical or a
trifluoromethyl radical.
[0043] According to the present invention, preference is given to
the compounds of formula (I) in which R.sub.3 represents a chlorine
atom or a methoxy radical.
[0044] According to the present invention, preference is given to
the compounds of formula (I) in which R.sub.4 represents a hydrogen
atom or is in the 3-position of the phenyl and represents a methoxy
radical.
[0045] According to the present invention, preference is given to
the compounds of formula (I) in which R.sub.5 represents a
dimethylamino group, an azetidin-1-yl radical or a methoxy
radical.
[0046] According to the present invention, preference is given to
the compounds of formula (I) in which R.sub.6 is in the 2-position
of the phenyl and represents a methoxy radical.
[0047] According to the present invention, preference is given to
the compounds of formula (I) in which R.sub.7 represents a methoxy
radical.
[0048] Preference is more particularly given to the compounds of
formula (I) in which:
[0049] R.sub.1 represents a chlorine atom or a methyl radical;
[0050] R.sub.2 represents a hydrogen atom or is in the 6-position
of the indol-2-one and represents a chlorine atom or a methyl
radical;
[0051] R.sub.3 represents a methoxy radical;
[0052] R.sub.4 represents a hydrogen atom;
[0053] R.sub.5 represents a dimethylamino group;
[0054] R.sub.6 is in the 2-position of the phenyl and represents a
methoxy radical;
[0055] R.sub.7 represents a methoxy radical; and their solvates
and/or hydrates.
[0056] According to the present invention, preference is given to
the compounds of formula (I) in the form of optically pure isomers,
the carbon atom in the 3-position of the indol-2-one has either the
(R) configuration or the (S) configuration.
[0057] Preference is most particularly given to the levorotatory
isomer of the compounds of formula (I).
[0058] The following compounds:
[0059]
(3S)-4-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphe-
nyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylmorpholine-3-carboxamide-
, levorotatory isomer;
[0060]
(3S)-4-[6-Chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphe-
nyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylmorpholine-3-ca-
rboxamide, levorotatory isomer;
[0061]
(3S)-4-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphe-
nyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylmorpholine-3-ca-
rboxamide, levorotatory isomer;
[0062] and their solvates and/or hydrates are more particularly
preferred.
[0063] According to another of its aspects, the subject of the
present invention is a process for the preparation of the compounds
of formula (I), their solvates and/or their hydrates, characterized
in that:
[0064] a compound of formula: 3
[0065] in which R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
as defined for a compound of formula (I), is reacted, in the
presence of a base, with a halide of formula: 4
[0066] in which R.sub.6 and R.sub.7 are as defined for a compound
of formula (I) and Hal represents a halogen atom.
[0067] The reaction is carried out in the presence of a strong
base, such as a metal hydride, for example sodium hydride, or an
alkali metal alkoxide, for example potassium tert-butoxide, in an
anhydrous solvent, such as N,N-dimethylformamide or
tetrahydrofuran, and at a temperature of between -70.degree. C. and
+60.degree. C. The reaction is preferably carried out by using a
compound of formula (III) in which Hal=Cl.
[0068] The compounds of formula (I) thus obtained can subsequently
be separated from the reaction mixture and purified according to
conventional methods, for example by crystallization or
chromatography.
[0069] The compounds of formula (II) are prepared by the reaction
of a 3-halo-1,3-dihydro-2H-indol-2-one compound of formula: 5
[0070] in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as
defined for a compound of formula (I) and Hal represents a halogen
atom, preferably chlorine or bromine, with a compound of formula:
6
[0071] in which R.sub.5 is as defined for a compound of formula
(I). The reaction is carried out in the presence of a base, such as
diisopropylethylamine or triethylamine, in an inert solvent, such
as dichloromethane or tetrahydrofuran or a mixture of these
solvents, and at a temperature of between ambient temperature and
the reflux temperature of the solvent.
[0072] The compounds of formula (III) are known or prepared by
known methods, such as those disclosed in EP-0 469 984 B and WO
95/18105. For example, the compounds of formula (III) can be
prepared by halogenation of the corresponding benzenesulfonic acids
or of their salts, for example of their sodium or potassium salts.
The reaction is carried out in the presence of a halogenating
agent, such as phosphorus oxychloride, thionyl chloride, phosphorus
trichloride, phosphorus tribromide or phosphorus pentachloride,
without a solvent or in an inert solvent, such as a halogenated
hydrocarbon or N,N-dimethylformamide, and at a temperature of
between -10.degree. C. and 200.degree. C.
[0073] 2,4-Dimethoxybenzenesulfonyl chloride is prepared according
to J. Am. Chem. Soc., 1952, 74, 2008. 3,4-Dimethoxybenzenesulfonyl
chloride is commercially available or prepared according to J. Med.
Chem., 1977, 20 (10), 1235-1239.
[0074] The compounds of formula (IV) are known and are prepared
according to known methods, such as those disclosed in WO
95/18105.
[0075] For example, a compound of formula: 7
[0076] in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as
defined for a compound of formula (I), is converted into a compound
of formula (IV) in which Hal=Cl by the action of thionyl chloride
in the presence of a base, such as pyridine, in an inert solvent,
such as dichloromethane, and at a temperature between 0.degree. C.
and ambient temperature.
[0077] According to another example of the preparation of the
compounds of formula (IV), a compound of formula: 8
[0078] in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as
defined for a compound of formula (I), is converted into a compound
of formula (IV) by means of a halogenating agent, such as bromine,
according to the process described in Farm. Zh. (Kiev), 1976, 5,
30-33.
[0079] The compounds of formula (VI) are known and are prepared
according to known methods, such as those disclosed in WO
95/18105.
[0080] For example, a compound of formula (VI) is prepared by
reaction of a 1H-indole-2,3-dione derivative of formula: 9
[0081] in which R.sub.1 and R.sub.2 are as defined for a compound
of formula (I), with an organomagnesium derivative of formula:
10
[0082] in which R.sub.3 and R.sub.4 are as defined for a compound
of formula (I) and Hal represents a halogen atom, preferably
bromine or iodine, in an inert solvent, such as tetrahydrofuran or
diethyl ether, and at a temperature of between 0.degree. C. and the
reflux temperature of the solvent.
[0083] A compound of formula (VI) in which R.sub.3 is as defined
for a compound of formula (I) and R.sub.4, which is other than
hydrogen, is in the 3- or 6-position of the phenyl can also be
prepared by the reaction of a compound of formula: 11
[0084] in which R.sub.3 is as defined for a compound of formula (I)
and R.sub.4 is in the 2- or 5-position of the phenyl, with a
lithium derivative, such as n-butyllithium, and then the lithiated
intermediate thus obtained is reacted with a compound of formula
(VIII). The reaction is carried out in a solvent, such as diethyl
ether, tetrahydrofuran, hexane or a mixture of these solvents, at a
temperature of between -70.degree. C. and ambient temperature.
[0085] The 1H-indole-2,3-dione derivatives (VIII) are commercially
available or prepared according to the methods described in
Tetrahedron Letters, 1998, 39, 7679-7682; Tetrahedron Letters,
1994, 35, 7303-7306; J. Org. Chem., 1977, 42 (8), 1344-1348; J.
Org. Chem., 1952, 17, 149-156; J. Am. Chem. Soc., 1946, 68,
2697-2703; Organic Syntheses, 1925, V, 71-74 and Advances in
Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Academic
Press, New York, 1975, 18, 2-58.
[0086] The organomagnesium derivatives (IX) are prepared according
to conventional methods well known to a person skilled in the
art.
[0087] A compound of formula (VI) can also be prepared by air
oxidation of a compound of formula (VII) in the presence of a base,
such as sodium hydride, and in the presence of dimethyl
disulfide.
[0088] Specifically, the compounds of formula (VI) in which
R.sub.3=(C.sub.1-C.sub.2)alkoxy and R.sub.4=H or else
R.sub.3=R.sub.4=(C.sub.1-C.sub.2)alkoxy with R.sub.4 in the 3- or
6-position of the phenyl, R.sub.2 is other than a halogen atom and
R.sub.1 is as defined for a compound of formula (I) can be prepared
by following the process described in SCHEME 1. 12
[0089] In stage a1 of SCHEME 1, a compound of formula (X) is first
of all reacted with a lithium derivative, such as n-butyllithium,
in the absence or in the presence of a base, such as
N,N,N',N'-tetramethylenediamine, and then the lithiated
intermediate thus obtained is reacted with diethyl oxalate to give
the compound of formula (XI). The reaction is carried out in an
inert solvent, such as diethyl ether or tetrahydrofuran, and at a
temperature of between -70.degree. C. and ambient temperature.
[0090] In stage b1, a compound of formula (XII) is first of all
reacted with two equivalents of a lithium derivative, such as
tert-butyllithium, and then the lithiated intermediate obtained is
reacted with the compound of formula (XI) to give the expected
compound of formula (VI). The reaction is carried out in an inert
solvent, such as diethyl ether or tetrahydrofuran, and at a
temperature of between -70.degree. C. and ambient temperature.
[0091] The compounds of formula (X) are commercially available or
are synthesized in a conventional way.
[0092] The compounds of formula (XII) are prepared by reaction of
the corresponding aniline derivatives with di-tert-butyl
dicarbonate according to conventional methods.
[0093] The compounds of formula (VII) are known and are prepared
according to known methods, such as those disclosed in WO 95/18105
or in J. Org. Chem., 1968, 33, 1640-1643.
[0094] The compounds of formula (V) are known or are prepared
according to known methods. Thus, for example, the compounds of
formula (V) in which R.sub.5 represents an ethylamino or
dimethylamino group or an azetidin-1-yl radical are prepared
according to SCHEME 2 below, in which Pr represents an N-protecting
group, in particular benzyl or tert-butoxycarbonyl, and R
represents a (C.sub.1-C.sub.2)alkyl. 13
[0095] In stage a2 of SCHEME 1, an ester of formula (XIII) is
esterified according to conventional methods, to obtain an acid of
formula (XIV).
[0096] The acid (XIV) is reacted in stage b2 with ethylamine,
dimethylamine or azetidine according to conventional peptide
coupling methods to give the compound (XV), which is deprotected in
stage c2, according to known methods, to give an expected compound
of formula (V).
[0097] A compound of formula (XIV) may also be prepared by
protecting, according to conventional methods,
(3S)-morpholine-3-carboxylic acid; the latter is prepared according
to the process described in Bull. Chem. Soc. Jpn. 1987, 60 (8),
2963-2965.
[0098] The compounds of formula (V) in which R.sub.5 represents a
(C.sub.1-C.sub.2)alkoxy are obtained by various known methods, in
particular by deprotection of the compounds of formula (XIII).
[0099] The chiral compounds of formula (XIII) are prepared from
(S)-serine according to the process described in J. Chem. Soc.
Perkin Trans I, 1985, 2577-2580.
[0100] When it is desired to prepare an optically pure compound of
formula (I), an optically pure compound of formula (II) is
preferably reacted with a compound of formula (III) according to
the process of the invention.
[0101] The optically pure compounds of formula (II) are prepared by
reaction of the racemic compound of formula (IV) with an optically
pure compound of formula (V), followed by separation of the mixture
of diastereoisomers according to conventional methods, for example
by crystallization or chromatography.
[0102] Alternatively, the mixture of diastereoisomers of the
compound of formula (II) can be reacted with the compound of
formula (III) and the mixture of diastereoisomers of the compound
of formula (I) thus obtained can be separated.
[0103] During any one of the stages for the preparation of the
compounds of formula (I) or of the intermediate compounds of
formula (II), (IV), (V) or (VI), it may be necessary and/or
desirable to protect the reactive or sensitive functional groups,
such as amine, hydroxyl or carboxyl groups, present on any one of
the molecules concerned. This protection can be achieved by using
conventional protecting groups, such as those described in
Protective Groups in Organic Chemistry, J. F. W. McOmie, published
by Plenum Press, 1973, in Protective Groups in Organic Synthesis,
T. W. Greene and P. G. M. Wutts, published by John Wiley and Sons,
1991 or in Protecting Groups, Kocienski P. J., 1994, Georg Thieme
Verlag. The protecting groups can be removed at an appropriate
subsequent stage using methods known to a person skilled in the art
which do not affect the remainder of the molecule concerned.
[0104] The N-protecting groups optionally used are conventional
N-protecting groups well known to a person skilled in the art, such
as, for example, the tert-butoxycarbonyl, fluorenylmethoxycarbonyl,
benzyl, benzhydrylidene or benzyloxycarbonyl group.
[0105] The compounds of formula (II) are novel and form part of the
invention.
[0106] Thus, according to another of its aspects, a subject of the
invention is compounds of formula: 14
[0107] in which:
[0108] R.sub.1 represents a halogen atom; a (C.sub.1-C.sub.4)alkyl;
a (C.sub.1C.sub.4)alkoxy; a trifluoromethyl radical; or a
trifluoromethoxy radical;
[0109] R.sub.2 represents a hydrogen atom; a halogen atom; a
(C.sub.1-C.sub.4)alkyl; a (C.sub.1-C.sub.4)alkoxy; or a
trifluoromethyl radical;
[0110] or else R.sub.2 is in the 6-position of the indol-2-one ring
and R.sub.1 and R.sub.2 together represent the bivalent
trimethylene radical;
[0111] R.sub.3 represents a halogen atom; a hydroxyl; a
(C.sub.1-C.sub.2)alkyl; a (C.sub.1-C.sub.2)alkoxy; or a
trifluoromethoxy radical;
[0112] R.sub.4 represents a hydrogen atom; a halogen atom; a
(C.sub.1-C.sub.2)alkyl; or a (C.sub.1-C.sub.2)alkoxy;
[0113] or else R.sub.4 is in the 3-position of the phenyl and
R.sub.3 and R.sub.4 together represent the methylenedioxy
radical;
[0114] R.sub.5 represents an ethylamino group; a dimethylamino
group; an azetidin-1-yl radical; or a (C.sub.1-C.sub.2) alkoxy;
[0115] and their salts with inorganic or organic acids, in the form
of optically pure isomers or in the form of a mixture of
diastereoisomers.
[0116] The salts of the compounds of formula (II) comprise those
with inorganic or organic acids which make possible suitable
separation or crystallization of the compounds of formula (II),
such as the hydrochloride, hydrobromide, oxalate, maleate,
succinate, fumarate, citrate or acetate.
[0117] The compounds of above formula (I) also comprise those in
which one or more hydrogen or carbon atoms have been replaced by
their radioactive isotope, for example tritium or carbon-14. Such
labeled compounds are of use in research, metabolism or
pharmacokinetic studies or in biochemical assays as receptor
ligand.
[0118] The compounds according to the invention have formed the
subject of biochemical studies.
[0119] The affinity of the compounds of formula (I) according to
the invention for arginine-vasopressin V.sub.1b receptors was
determined in vitro by using the method described by Y. De Keyser
et al., FEBS Letters, 1994, 356, 215-220. This method consists in
studying in vitro the displacement of tritiated
arginine-vasopressin ([.sup.3H]-AVP) at the V.sub.1b receptors
present on adenohypophysal membrane or cell preparations carrying
rat or human V.sub.1b receptors. The 50% inhibitory concentrations
(IC.sub.50) for the attachment of tritiated arginine-vasopressin of
the compounds according to the invention are low and vary from
10.sup.-6 to 10.sup.-9M, more particularly 10.sup.-8M.
[0120] The affinity of the compounds of formula (I) according to
the invention for arginine-vasopressin V.sub.1a receptors was
determined in vitro using the method described by M. Thibonnier et
al., J. Biol. Chem., 1994, 269, 3304-3310. This method consists in
studying in vitro the displacement of tritiated
arginine-vasopressin ([.sup.3H]-AVP) at the V.sub.1a receptors
present on membrane or cell preparations carrying rat or human
V.sub.1a receptors. Some of the compounds of formula (I) also
exhibit an affinity for arginine-vasopressin V.sub.1a receptors,
with IC.sub.50 values which vary from 10.sup.-6 to 10-.sup.9M, more
particularly 10.sup.-7M.
[0121] The affinity of the compounds of formula (I) according to
the invention for vasopressin V.sub.2 receptors has also been
studied (method described by M. Birnbaumer et al., Nature (Lond.),
1992, 357, 333-335). The compounds studied have little or no
affinity for the V.sub.2 receptors.
[0122] The compounds of the present invention are in particular
active ingredients of pharmaceutical compositions, the toxicity of
which is compatible with their use as medicaments.
[0123] According to another of its aspects, the present invention
relates to the use of the compounds of formula (I), of their
solvates and/or of their hydrates which are pharmaceutically
acceptable for the preparation of medicaments intended for the
treatment of any pathology where arginine-vasopressin and/or its
V.sub.1b receptors or both its V.sub.1b receptors and its V.sub.1a
receptors are implicated.
[0124] According to another of its aspects, the present invention
relates to the use of the compounds of formula (I), of their
solvates and/or of their hydrates which are pharmaceutically
acceptable in the preparation of medicaments intended for the
treatment of pathologies of the cardiovascular system, of the
central nervous system, of the renal system or of the gastric
system and of small cell lung cancers, obesity, type-II diabetes,
insulin resistance, hypertriglyceridemia, atherosclerosis,
Cushing's syndrome or any pathology resulting from stress and
chronic stress conditions.
[0125] Thus, the compounds according to the invention may be used,
in man or in animals, in the treatment or prevention of various
vasopressin-dependent conditions, such as cardiovascular
conditions, for example hypertension, pulmonary hypertension,
cardiac insufficiency, myocardial infarction or coronary vasospasm,
in particular in smokers, Raynaud's syndrome, unstable angina and
PTCA (percutaneous transluminal coronary angioplasty), cardiac
ischemia or hemostasis disturbances; conditions of the central
nervous system, such as migraine, cerebral vasospasm, cerebral
hemorrhage, cerebral edema, depression, anxiety, stress,
obsessive-compulsive disorder, panic attacks, psychotic states or
memory disorders, for example; conditions of the renal system, such
as renal vasospasm, necrosis of the renal cortex; nephrogenic
diabetes insipidus; conditions of the gastric system, such as
gastric vasospasm, cirrhosis of the liver, ulcers or the pathology
of vomiting, for example nausea, including nausea due to
chemotherapy or travel sickness; or diabetic nephropathy. The
compounds according to the invention can also be used in the
treatment of disorders of sexual behavior; in women, the compounds
according to the invention can be used to treat dysmenorrhoea or
premature labor. The compounds according to the invention can also
be used in the treatment of small cell lung cancers; hyponatremic
encephalopathy; pulmonary syndrome, Meniere's disease; glaucoma,
cataracts; obesity; type-II diabetes; atherosclerosis; Cushing's
syndrome; insulin resistance, or hypertriglyceridemia, or in
post-operative treatments, in particular after abdominal
surgery.
[0126] The compounds according to the invention can also be used in
the treatment or prevention of any pathology resulting from stress,
such as fatigue and its syndromes, ACTH-dependent disorders,
cardiac disorders, pain, modifications in gastric emptying, in
fecal excretion (colitis, irritable bowel syndrome or Crohn's
disease) or in acid secretion, hyperglycemia, immunosuppression,
inflammatory processes (rheumatoid arthritis and osteoarthritis),
multiple infections, cancers, asthma, psoriasis, allergies and
various neuropsychiatric disorders, such as anorexia nervosa,
bulimia, mood disorders, depression, anxiety, sleep disorders,
panic states, phobias, obsession, disorders of pain perception
(fibromyalgia), neurodegenerative diseases (Alzheimer's disease,
Parkinson's disease or Huntington's disease), substance dependence,
hemorrhagic stress, muscle spasms or hypoglycemia. The compounds
according to the invention can also be used in the treatment or
prevention of chronic stress conditions, such as immunodepression,
fertility disorders or dysfunctionings of the
hypothalamo-pituitaryadrena- l axis.
[0127] The compounds according to the invention can also be used as
psychostimulants, resulting in an increase in alertness or
emotional reactivity to the surroundings and making adaptation
easier.
[0128] The compounds of above formula (I), their solvates and/or
their hydrates which are pharmaceutically acceptable can be used at
daily doses of 0.01 to 100 mg per kilo of body weight of the mammal
to be treated, preferably at daily doses of 0.1 to 50 mg/kg. In
man, the dose can preferably vary from 0.1 to 4000 mg per day, more
particularly from 0.5 to 1000 mg, depending upon the age of the
subject to be treated or the type of treatment; prophylactic or
curative.
[0129] For their use as medicaments, the compounds of formula (I)
are generally administered in dosage units. Said dosage units are
preferably formulated in pharmaceutical compositions in which the
active ingredient is mixed with one or more pharmaceutical
excipients.
[0130] Thus, according to another of its aspects, the present
invention relates to pharmaceutical compositions including, as
active ingredient, a compound of formula (I), one of its solvates
and/or one of its hydrates which are pharmaceutically
acceptable.
[0131] In the pharmaceutical compositions of the present invention
for administration by the oral, sublingual, inhaled, subcutaneous,
intramuscular, intravenous, transdermal, local or rectal route, the
active ingredients can be administered in single-dose
administration forms, as a mixture with conventional pharmaceutical
vehicles, to animals and human beings. The appropriate single-dose
administration forms comprise forms by the oral route, such as
tablets, gelatin capsules, powders, granules and oral solutions or
suspensions, sublingual and buccal administration forms, aerosols,
topical administration forms, implants, subcutaneous,
intramuscular, intravenous, intranasal or intraocular
administration forms and rectal administration forms.
[0132] When a solid composition is prepared in the form of tablets
or gelatin capsules, a mixture of pharmaceutical excipients is
added to the micronized or nonmicronized active ingredient, which
mixture can be composed of diluents, such as, for example, lactose,
microcrystalline cellulose, starch or dicalcium phosphate, of
binders, such as, for example, polyvinylpyrrolidone or
hydroxypropylmethylcellulose, of disintegrating agents, such as
crosslinked polyvinylpyrrolidone or crosslinked
carboxymethylcellulose, of flow agents, such as silica or talc, or
of lubricants, such as magnesium stearate, stearic acid, glyceryl
tribehenate or sodium stearylfumarate.
[0133] Wetting agents or surfactants, such as sodium lauryl
sulfate, polysorbate 80 or poloxamer 188, can be added to the
formulation.
[0134] The tablets can be prepared by various techniques: direct
tableting, dry granulation, wet granulation or hot-melt.
[0135] The tablets can be bare or sugar-coated (with sucrose, for
example) or coated with various polymers or other appropriate
materials.
[0136] The tablets can have a flash, delayed or sustained release
by preparing polymeric matrices or by using specific polymers when
forming the thin film.
[0137] The gelatin capsules may be soft or hard and may or may not
be coated with a thin film, so as to have a flash, sustained or
delayed activity (for example via an enteric form).
[0138] They can comprise not only a solid formulation formulated as
above for tablets but also liquids or semi-solids.
[0139] A preparation in the form of a syrup or elixir can comprise
the active ingredient in conjunction with a sweetener, preferably a
calorie-free sweetener, methylparaben and propylparaben, as
antiseptic, a flavoring agent and an appropriate colorant.
[0140] The water-dispersible powders or granules can comprise the
active ingredient as a mixture with dispersing agents, wetting
agents or suspending agents, such as polyvinylpyrrolidone, as well
as with sweeteners or flavor enhancers.
[0141] For rectal administration, recourse is had to suppositories
which are prepared with binders which melt at the rectal
temperature, for example cocoa butter or polyethylene glycols.
[0142] For parenteral, intranasal or intraocular administration,
use is made of aqueous suspensions, isotonic saline solutions or
sterile and injectable solutions which comprise pharmacologically
compatible dispersing agents and/or solubilizing agents, for
example propylene glycol.
[0143] Thus, to prepare an aqueous solution which can be injected
by the intravenous route, use may be made of a cosolvent, such as,
for example, an alcohol, such as ethanol, or a glycol, such as
polyethylene glycol or propylene glycol, and of a hydrophilic
surfactant, such as polysorbate 80 or poloxamer 188. To prepare an
oily solution which can be injected by the intramuscular route, the
active ingredient can be dissolved with a triglyceride or a
glyceryl ester.
[0144] For local administration, use may be made of creams,
ointments, gels, eyewashes or sprays.
[0145] For transdermal administration, use may be made of patches
in multilaminar or reservoir form, in which the active ingredient
can be in alcoholic solution, or sprays.
[0146] For administration by inhalation, use is made of an aerosol
comprising, for example, sorbitan trioleate or oleic acid and
trichlorofluoromethane, dichlorofluoromethane,
dichlorotetrafluoroethane, freon substitutes or any other
biologically compatible propellant gas; use may also be made of a
system comprising the active ingredient, alone or in combination
with an excipient, in powder form.
[0147] The active ingredient can also be presented in the form of a
complex with a cyclodextrin, for example .alpha.-, .beta.- or
.gamma.-cyclodextrin or 2-hydroxypropyl-.beta.-cyclodextrin.
[0148] The active ingredient can also be formulated in the form of
microcapsules or microspheres, optionally with one or more vehicles
or additives.
[0149] Use may be made of implants among the sustained-release
forms of use in the case of chronic treatments. These implants can
be prepared in the form of an oily suspension or in the form of a
suspension of microspheres in an isotonic medium.
[0150] The active ingredient of formula (I) is present in each
dosage unit in the amounts suited to the daily doses envisaged. In
general, each dosage unit is suitably adjusted according to the
dosage and the type of administration provided, for example
tablets, gelatin capsules and the like, sachets, ampules, syrups
and the like, or drops, so that such a dosage unit comprises from
0.1 to 1000 mg of active ingredient, preferably from 0.5 to 250 mg,
which has to be administered one to four times daily.
[0151] Although these dosages are examples of average situations,
there may be specific cases where higher or lower dosages are
appropriate; such dosages also form part of the invention.
According to the usual practice, the dosage appropriate to each
patient is determined by the physician according to the method of
administration and the age, the weight and the response of said
patient.
[0152] The compositions of the present invention can comprise, in
addition to the compounds of formula (I), their solvates and/or
their hydrates which are pharmaceutically acceptable, other active
ingredients which can be of use in the treatment of the disorders
or diseases indicated above.
[0153] Thus, another subject of the present invention is
pharmaceutical compositions comprising several active ingredients
in combination, one of which is a compound according to the
invention.
[0154] Thus, according to the present invention, pharmaceutical
compositions can be prepared which comprise a compound according to
the invention in combination with a compound which has an effect on
the CRF receptors.
[0155] The compounds according to the invention can also be used
for the preparation of compounds for veterinary use.
[0156] The following PREPARATIONS and EXAMPLES illustrate the
invention without, however, limiting it.
[0157] Use is made, in the Preparations and in the Examples, of the
following abbreviations:
[0158] ether: diethyl ether
[0159] iso ether: diisopropyl ether
[0160] DMF: N,N-dimethylformamide
[0161] THF: tetrahydrofuran
[0162] DCM: dichloromethane
[0163] AcOEt: ethyl acetate
[0164] DIPEA: diisopropylethylamine
[0165] TFA: trifluoroacetic acid
[0166] Boc: tert-butoxycarbonyl
[0167] Cbz: benzyloxycarbonyl
[0168] BOP: benzotriazol-1-yloxytris(dimethyl-amino)phosphonium
hexafluorophosphate
[0169] PyBOP: benzotriazol-1-yloxytripyrrolidino-phosphonium
hexafluorophosphate
[0170] DCC: 1,3-dicyclohexylcarbodiimide
[0171] HOBT: 1-hydroxybenzotriazole hydrate
[0172] M.p.: melting point
[0173] AT: ambient temperature
[0174] B.p.: boiling point
[0175] HPLC: high performance liquid chromatography.
[0176] The proton magnetic resonance spectra (.sup.1H NMR) are
recorded at 200 MHz in d.sub.6-DMSO using the d.sub.6-DMSO peak as
reference. The chemical shifts .delta. are expressed in parts per
million (ppm). The signals observed are expressed thus: s: singlet;
bs: broad singlet; d: doublet; dd: double doublet; t: triplet; q:
quartet; up: unresolved peak; mt: multiplet.
[0177] The mass spectra indicate the value MH.sup.+.
PREPARATIONS
[0178] Preparations of the compounds of formula (IV).
[0179] Preparation 1.1
[0180]
3,5-Dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one.
[0181] (IV): R.sub.1=Cl; R.sub.2=H; R.sub.3=OCH.sub.3; R.sub.4=H;
Hal=Cl.
[0182] A)
5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-on-
e.
[0183] This compound is prepared according to the procedure
disclosed in WO 95/18105. A solution of 2-methoxyphenylmagnesium
bromide is prepared from 16 g of magnesium in 35 ml of ether and
from a solution of 124 g of 1-bromo-2-methoxybenzene in 175 ml of
ether. This solution is added dropwise under an argon atmosphere to
a mixture, cooled beforehand in an ice bath, of 30 g of
5-chloro-1H-indole-2,3-dione in 250 ml of THF and then the mixture
is left stirring while allowing the temperature to rise to AT.
After stirring for 1 hour at AT, the reaction mixture is slowly
poured onto a saturated NH.sub.4Cl solution and the THF is
evaporated under vacuum. The precipitate formed is filtered off and
is washed with iso ether. 42 g of the expected product are
obtained, which product is used as is in the following stage.
[0184] B)
3,5-Dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one.
[0185] This compound is prepared according to the procedure
disclosed in WO 95/18105. A mixture of 12.71 g of the compound
obtained in the preceding stage in 105 ml of DCM is cooled to
0.degree. C., 5.3 ml of pyridine are added and then 4.9 ml of
thionyl chloride are added. After stirring for 30 minutes, water is
added to the reaction mixture and the DCM is evaporated under
vacuum. The precipitate formed is filtered off, washed three times
with water and then three times with iso ether, and dried. 13.66 g
of the expected product are obtained, which product is used as
is.
[0186] Preparation 1.2
[0187]
3,6-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-on-
e
[0188] (IV): R.sub.1=CH.sub.3; R.sub.2=6-Cl; R.sub.3=OCH.sub.3;
R.sub.4=H; Hal=Cl.
[0189] A) 6-Chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one
and 4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one.
[0190] 8.5 ml of chlorine are introduced into 320 ml of DCM, cooled
to -70.degree. C., then a solution of 24 ml of ethyl
methylthioacetate in 60 ml of DCM is added over 20 minutes at
-70.degree. C. and the mixture is left stirring for 15 minutes at
-70.degree. C. A solution of 52.64 g of 3-chloro-4-methylaniline in
100 ml of DCM is subsequently added at -70.degree. C. over 30
minutes and the mixture is left stirring for 1 hour 45 minutes at
-70.degree. C. Finally, 41.3 ml of triethylamine are added at
-70.degree. C. and the mixture is left stirring for 1 hour while
allowing the temperature to rise to AT. The reaction mixture is
washed twice with 250 ml of water, the organic phase is dried over
MgSO.sub.4 and the solvent is evaporated under vacuum. The residue
is taken up in a mixture of 600 ml of ether and 130 ml of 2N HCl
and the mixture is left stirring for 72 hours at AT. An insoluble
material is filtered off, the filtrate is separated by settling,
the organic phase is washed twice with water and dried over
MgSO.sub.4, and the solvent is evaporated under vacuum. The residue
is chromatographed on silica gel, elution being carried out with
DCM and then with a DCM/AcOEt (85/15; v/v) mixture. The mixture
obtained is rechromatographed on silica gel, elution being carried
out with DCM and then with a DCM/AcOEt (95/5; v/v) mixture. The two
isomers are separated:
[0191] the less polar isomer, which is
6-chloro-5-methyl-3-methylthio-1,3-- dihydro-2H-indol-2-one, and
1.16 g are obtained,
[0192] the more polar isomer, which is
4-chloro-5-methyl-3-methylthio-1,3-- dihydro-2H-indol-2-one, and
0.72 g is obtained.
[0193] B) 6-Chloro-5-methyl-1H-indole-2,3-dione.
[0194] A mixture of 1.16 g of
6-chloro-5-methyl-3-methylthio-1,3-dihydro-2- H-indol-2-one,
obtained in the preceding stage, and 0.681 g of N-chlorosuccinimide
in 100 ml of carbon tetrachloride is heated at reflux for 1 hour.
The reaction mixture is concentrated under vacuum and the residue
is taken up in a mixture of 80 ml of THF and 20 ml of water and
then heated at reflux for 16 hours. The THF is evaporated under
vacuum, the remaining aqueous phase is extracted with AcOEt, the
organic phase is washed with water and with a saturated NaCl
solution and dried over Na.sub.2SO.sub.4, and the solvent is
evaporated under vacuum. The residue is chromatographed on silica
gel, elution being carried out with DCM and then with the gradient
of the DCM/AcOEt mixture up to (85/15; v/v). 0.793 g of the
expected product is obtained, M.p.=264.degree. C.
[0195] C)
6-Chloro-3-hydroxy-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-i-
ndol-2-one.
[0196] A solution of 2-methoxyphenylmagnesium bromide is prepared
from 0.687 g of magnesium in 1.5 ml of ether and from a solution of
5.35 g of 1-bromo-2-methoxybenzene in 7.55 ml of ether. This
solution is added dropwise, under an argon atmosphere, to a
mixture, cooled beforehand in an ice bath, of 1.4 g of the compound
obtained in the preceding stage in 14 ml of THF and then the
mixture is left stirring while allowing the temperature to rise to
AT. After stirring for 1 hour at AT, the reaction mixture is slowly
poured onto a saturated NH.sub.4Cl solution, the THF is evaporated
under vacuum, extraction is carried out with AcOEt, the organic
phase is washed with water and with a saturated NaCl solution and
dried over Na.sub.2SO.sub.4, and the AcOEt is evaporated under
vacuum. The residue is chromatographed on silica gel, elution being
carried out with DCM and then with a DCM/MeOH (98/2; v/v) mixture.
1.6 g of the expected product are obtained after crystallization
from a THF/MeOH mixture, M.p.=266.degree. C.
[0197] D)
3,6-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-
-one.
[0198] A suspension of 1.7 g of the compound obtained in the
preceding stage in 10 ml of DCM is cooled in an ice bath, 1.4 ml of
pyridine and then 1.4 ml of thionyl chloride are added and the
mixture is left stirring at AT. Water is added to the reaction
mixture; after separation by settling, the organic phase is washed
with water to pH=7, dried over Na.sub.2SO.sub.4 and the solvent is
evaporated under vacuum. 1.09 g of the expected product are
obtained after crystallization from a DCM/iso ether mixture.
[0199] Preparation 1.3
[0200]
3,5-Dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-on-
e.
[0201] (IV): R.sub.1=Cl; R.sub.2=6-CH.sub.3; R.sub.3=OCH.sub.3;
R.sub.4=H; Hal=Cl.
[0202] A) Ethyl 2-(2-methoxyphenyl)-2-oxoacetate.
[0203] A solution of 27 g of 1-bromo-2-methoxybenzene in 270 ml of
ether is cooled to -70.degree. C. under an argon atmosphere, 90 ml
of a 1.6M solution of n-butyllithium in pentane are added dropwise
and then the mixture is left stirring for 45 minutes. 78 ml of
diethyl oxalate are rapidly added and the mixture is left stirring
while allowing the temperature to rise to AT. After stirring for 1
hour at AT, a saturated NH.sub.4Cl solution is added to the
reaction mixture, separation by settling is carried out, the
aqueous phase is extracted with ether, the combined organic phases
are washed with water and with a saturated NaCl solution and dried
over Na.sub.2SO.sub.4, and the solvents are evaporated under
vacuum. The excess diethyl oxalate is removed by vacuum
distillation (B.p.=87.degree. C. under 2000 Pa). The resulting
product is chromatographed on silica gel, elution being carried out
with a DCM/hexane (50/50; v/v) mixture and then with DCM. The
product obtained is purified by vacuum distillation. 13 g of the
expected product are obtained, B.p.=110.degree. C. under 3 Pa.
[0204] B)
5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-i-
ndol-2-one.
[0205] a) tert-Butyl 4-chloro-3-methylphenyl-carbamate.
[0206] A mixture of 10 g of 4-chloro-3-methylaniline and 15.26 g of
di-tert-butyl dicarbonate in 50 ml of dioxane is left stirring for
24 hours at AT. The reaction mixture is concentrated under vacuum
and the residue is chromatographed on silica gel, elution being
carried out with the gradient of the DCM/hexane mixture from
(50/50; v/v) to (70/30; v/v). 5.6 g of the expected product are
obtained, which product is used as is.
[0207] b) A solution of 5 g of tert-butyl
4-chloro-3-methylphenylcarbamate in 45 ml of ether is cooled to
-70.degree. C. under an argon atmosphere, 30 ml of a 1.5M solution
of tert-butyllithium in pentane are added dropwise, and the mixture
is left stirring for 1 hour while raising the temperature to
-10.degree. C. and left stirring at -10.degree. C. for 1 hour 45
minutes. The reaction mixture is cooled to -70.degree. C., a
solution of 5 g of the compound obtained in stage A in 25 ml of THF
is added dropwise, and the mixture is left stirring for 1 hour
while allowing the temperature to rise to -30.degree. C. and then
overnight while allowing the temperature to rise to AT. A saturated
NH.sub.4Cl solution is added to the reaction mixture, the THF is
evaporated, the resulting aqueous phase is extracted three times
with AcOEt, the organic phase is washed with water and with a
saturated NaCl solution and dried over Na.sub.2SO.sub.4, the
solvent is partially evaporated and the crystalline product is
filtered off. 2.6 g of the expected product are obtained,
M.p.=254-256.degree. C.
[0208] C)
3,5-Dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-
-one.
[0209] A mixture of 1.25 g of the compound obtained in stage B in
20 ml of DCM is cooled to 0.degree. C., 0.5 ml of pyridine is added
and then 0.47 ml of thionyl chloride is added, and the mixture is
left stirring for 1 hour after having allowed the temperature to
rise to AT. Water and DCM are added to the reaction mixture, after
separating by settling the organic phase is washed four times with
water and dried over Na.sub.2SO.sub.4, and the solvent is
evaporated under vacuum. 1.4 g of the expected product are
obtained.
[0210] Preparation of the compounds of formula (V).
[0211] Preparation 2.1
[0212] (3S) -N,N-Dimethylmorpholine-3-carboxamide.
[0213] (V): R.sub.5=-N(CH.sub.3).sub.2.
[0214] A) (S) -N-Benzylserine.
[0215] 28.5 ml of benzaldehyde are added dropwise to a solution of
30 g of (S)-serine in 150 ml of a 2M aqueous NaOH solution and the
mixture is left stirring for 2 hours at AT. The reaction mixture is
cooled to 4.degree. C., 3 g of sodium borohydride are added in
portions and the mixture is left stirring for 1 hour at 4.degree.
C. and then for 1 hour at AT. The reaction mixture is washed with
ether, the aqueous phase is acidified to pH=6.5 by addition of a
ION HCl solution and the precipitate formed is filtered off. 20 g
of the expected product are obtained after crystallization from
water.
[0216] B) (3S)-4-Benzyl-5-oxomorpholine-3-carboxylic Acid.
[0217] A mixture of 20 g of the compound obtained in the preceding
stage in 100 ml of water is cooled to 4.degree. C., 5 g of NaOH
pellets are added and then 10 ml of chloroacetyl chloride are added
dropwise and over 30 minutes. 30 ml of an aqueous 30%
(weight/weight) NaOH solution are then added and the reaction
mixture is heated at 30.degree. C. for 2 hours. The reaction
mixture is cooled to 4.degree. C., acidified to pH=1 by addition of
a ION HCl solution and the precipitate formed is filtered off. 9 g
of the expected product are obtained.
[0218] C) Ethyl Ester of (3S)-4-Benzyl-5-oxomorpholine-3-carboxylic
Acid.
[0219] This compound is prepared using the method described by B.
Neises and W. Steglich in Angew. Chem. Int. Ed. Engl., 1978, 17
(7), 522-524.
[0220] A mixture of 8 g of the compound obtained in the preceding
stage in 40 ml of DCM and 2 ml of DMF is cooled to 4.degree. C., 10
ml of EtOH, 1 g of 4-dimethyl-aminopyridine and 15 g of
1,3-dicyclohexylcarbodiimide are successively added, and then the
reaction mixture is left stirring for 18 hours at AT. The insoluble
material is filtered off and the filtrate is concentrated under
vacuum. The residue is taken up in DCM and the insoluble material
is again filtered off. The resulting organic phase is washed with
an aqueous 5% KHSO.sub.4 solution, with an aqueous 5% NaHCO.sub.3
solution, dried over Na.sub.2SO.sub.4 and the solvent is evaporated
under vacuum. The residue is chromatographed on silica gel, elution
being carried out with a DCM/AcOEt (95/5; v/v) mixture. 8 g of the
expected product are obtained.
[0221] D) Ethyl Ester of (3S)-4-Benzylmorpholine-3-carboxylic
Acid.
[0222] A solution of 7.8 g of the compound obtained in the
preceding stage in 80 ml of anhydrous THF is cooled to 4.degree. C.
under a nitrogen atmosphere, 22 ml of a 2M solution of
borane-dimethyl sulfide complex in THF are added and the reaction
mixture is left stirring while allowing the temperature to rise to
AT. After stirring for 3 hours at AT, water is added until the
gaseous emission ceases. The THF is evaporated under vacuum, the
resulting aqueous phase is alkalinized to pH=10 by addition of NaOH
pellets, extracted with ether, the organic phase is dried over
MgSO.sub.4 and the solvent is evaporated under vacuum. The residue
is chromatographed on silica gel, elution being carried out with a
DCM/AcOEt (99/1; v/v) mixture. 4.7 g of the expected product are
obtained.
[0223] E) (3S)-4-Benzylmorpholine-3-carboxylic Acid.
[0224] 7 ml of an aqueous. 50% NaOH solution are added at AT to a
solution of 4.5 g of the compound obtained in the preceding stage
in 20 ml of EtOH and the mixture is left stirring for 3 hours at
AT. The reaction mixture is acidified to pH=2 by addition of a
concentrated HCl solution and the mixture is concentrated under
vacuum. The resulting product is used as is in the next stage.
[0225] F) (3S)-4-Benzyl-N,N-dimethylmorpholine-3-carboxamide.
[0226] 9.81 g of PyBOP and then 10 ml of DIPEA are added at AT to a
mixture of the compound obtained in the preceding stage in 20 ml of
DCM and the mixture is left stirring for 30 minutes at AT.
Dimethylamine gas is then added by bubbling for 10 minutes and the
mixture is left stirring for 18 hours at AT. The reaction mixture
is concentrated under vacuum, the residue is extracted with AcOEt,
the organic phase is washed with an aqueous 5% Na.sub.2CO.sub.3
solution, with a saturated NaCl solution, dried over MgSO.sub.4 and
the solvent is concentrated under vacuum. The residue is
chromatographed on silica gel, elution being carried out with a
DCM/MeOH (98/2; v/v) mixture. 1.85 g of the expected product are
obtained.
[0227] G) (3S) -N,N-Dimethylmorpholine-3-carboxamide.
[0228] A mixture of 1.83 g of the compound obtained in the
preceding stage and 0.09 g of 10% palladium on carbon in 50 ml of
EtOH is hydrogenated at 30.degree. C. and at atmospheric pressure.
The catalyst is filtered through Celite and the filtrate is
concentrated under vacuum. 1 g of the expected product is
obtained.
[0229] .sup.1H NMR: DMSO-d.sub.6: .delta. (ppm) 2.85: s: 3H; 3.5:
s:3H; 3.2: mt: 2H; 3.3 to 4.3: up: 4H; 4.6: mt: 1H.
[0230] Preparations of the compounds of formula (II)
[0231] Preparation 3.1
[0232]
(3S)-4-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-y-
l]-N,N-dimethylmorpholine-3-carboxamide, mixture of
diastereoisomers.
[0233] (II): R.sub.1=Cl; R.sub.2=H; R.sub.3=OCH.sub.3; R.sub.4=H;
R.sub.5=--N(CH.sub.3).sub.2.
[0234] 1.75 g of the compound obtained in Preparation 1.1 and then
0.8 ml of triethylamine are added at AT to a solution of 0.9 g of
the compound obtained in Preparation 2.1 in 25 ml of DCM and the
mixture is left stirring for 48 hours at AT. The reaction mixture
is concentrated under vacuum, the residue is extracted with AcOEt,
the organic phase is washed with an aqueous 5% KHSO.sub.4 solution,
with an aqueous 5% Na.sub.2CO.sub.3 solution, with a saturated NaCl
solution, dried over MgSO.sub.4 and the solvent is evaporated under
vacuum. The residue is chromatographed on silica gel, elution being
carried out with a DCM/MeOH (98/5; v/v) mixture. 1.63 g of the
expected product are obtained.
[0235] .sup.1H NMR: DMSO-d.sub.6: .delta. (ppm): 2.0 to 2.8: up:
6H; 3.3:2s: 3H; 3.4 to 4.2: up: 7H; 6.4 to 8.0: mt: 7H; 10.0 to
10.5:2s: 1H.
[0236] Preparations 3.2 and 3.3
[0237]
(3S)-4-[6-Chloro-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H--
indol-3-yl]-N,N-dimethylmorpholine-3-carboxamide, isomer A and
isomer B.
[0238] (II): R.sub.1=CH.sub.3; R.sub.2=6-Cl; R.sub.3=OCH.sub.3;
R.sub.4=H; R.sub.5=--N(CH.sub.3).sub.2.
[0239] 1.02 g of the compound obtained in Preparation 2.1 and then
0.7 ml of triethylamine are added at AT to a solution of 0.62 g of
the compound obtained in Preparation 1.2 in 40 ml of DCM and the
mixture is left stirring for 18 hours at AT. The reaction mixture
is concentrated under vacuum, the residue is extracted with AcOEt,
the organic phase is washed with an aqueous 5% KHSO.sub.4 solution,
with an aqueous 5% Na.sub.2CO.sub.3 solution, with a saturated NaCl
solution, dried over MgSO.sub.4 and the solvent is evaporated under
vacuum. The residue is chromatographed over alumina, elution being
carried out with a DCM/MeOH (99/1; v/v) mixture. The two isomers
are separated:
[0240] the less polar, isomer A: compound of Preparation 3.2 which
is crystallized from a DCM/iso ether mixture and 0.4 g is obtained,
M.p.=237.degree. C.
[0241] .alpha..sub.D.sup.25=+106.degree. (c=0.1; chloroform).
[0242] .sup.1H NMR: DMSO-d.sub.6: .delta. (ppm): 2.1: bs: 3H; 2.5
to 2.9:2s: 6H; 3.3 to 4.2: up: 10H; 6.4: bs: 1H; 6.7: bs:1H; 6.8:
d: 1H; 7.0: t: 1H; 7.2: t: 1H; 7.9: d: 1H; 10.2: s: 1H.
[0243] the more polar, isomer B: compound of Preparation 3.3 which
is crystallized from a DCM/iso ether mixture and 0.73 g is
obtained, M.p.=177.degree. C.
[0244] .alpha..sub.D.sup.25 =-150.degree. (c=0.1; chloroform).
[0245] .sup.1H NMR: DMSO-d.sub.6: .delta. (ppm): 2.0: s: 3H; 2.2 to
2.6:2s: 6H; 3.4: s: 3H; 3.5 to 3.8: mt: 6H; 4.0: mt:1H; 6.5: s: 1H;
6.7: s: 1H; 6.8: d: 1H; 7.0: t: 1H; 7.2: t: 1H; 7.8: d: 1H; 10.0:
s: 1H.
[0246] Preparations 3.4 and 3.5
[0247]
(3S)-4-[5-Chloro-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H--
indol-3-yl]-N,N-dimethylmorpholine-3-carboxamide, isomer A and
isomer B.
[0248] (II): R.sub.1=Cl; R.sub.2=6-CH.sub.3; R.sub.3=OCH.sub.3;
R.sub.4=H; R.sub.5=--N(CH.sub.3).sub.2.
[0249] 1.13 g of DIPEA are added to a mixture of 1.4 g of the
compound obtained in Preparation 1.3 and 0.7 g of the compound
obtained in Preparation 2.1 in 15 ml of DCM and the mixture is left
stirring for 3 hours at AT. 0.65 g of DIPEA is added, the mixture
is left stirring for 48 hours at AT and the formation of a
precipitate is observed. The reaction mixture is concentrated under
vacuum, the residue is taken up in an aqueous 5% Na.sub.2CO.sub.3
solution, extracted twice with AcOEt, the organic phase is washed
with water, with a saturated NaCl solution, the precipitate present
in the organic phase corresponding to isomer A, less polar
compound, is filtered over aluminum, DCM/MeOH (95/5; v;v) (compound
of Preparation 3.4). The filtration liquors are chromatographed on
alumina, elution being carried out with a DCM/MeOH (95/5) mixture.
The two isomers are separated:
[0250] the less polar, isomer A: compound of Preparation 3.4 which
is added to the product previously obtained and crystallized from a
DCM/AcOEt/MeOH mixture to obtain 0.292 g, M.p.=230-238.degree.
C.
[0251] .alpha..sub.D.sup.25=+79.6.degree. (c=0.1; chloroform).
[0252] the more polar, isomer B: compound of Preparation 3.5 and
0.887 g is obtained.
[0253] .alpha..sub.D.sup.25=-100.degree. (c=0.1; chloroform).
EXAMPLES 1 AND 2
[0254]
(3S)-4-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphe-
nyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylmorpholine-3-carboxamide-
, isomer A and isomer B.
[0255] (I) R.sub.1 Cl; R.sub.2=H; R.sub.3=OCH.sub.3; R.sub.4=H;
R.sub.5=--N(CH.sub.3).sub.2; R.sub.6=2-OCH.sub.3;
R.sub.7=OCH.sub.3.
[0256] A mixture of 1.85 g of the compound obtained in Preparation
3.1 in 18 ml of DMF is cooled to 4.degree. C. under a nitrogen
atmosphere, 0.191 g of 60% sodium hydride in oil is added and the
mixture is left stirring for 30 minutes at 4.degree. C. 1.02 g of
2,4-dimethoxybenzenesulfonyl chloride are then added and the
mixture is left stirring for 3 hours at AT. 50 ml of water are
added to the reaction mixture, it is extracted with AcOEt, the
organic phase is washed with water, with a saturated NaCl solution,
dried over MgSO.sub.4 and the solvent is evaporated under vacuum.
The residue is chromatographed on silica gel, elution being carried
out with a DCM/MeOH (98/2; v/v) mixture. The two isomers are
separated:
[0257] the less polar, isomer A: compound of Example 1 which is
crystallized from hexane and 0.437 g is obtained, M.p.=156.degree.
C.
[0258] .alpha..sub.D.sup.25=+136.degree. (c=0.1; chloroform).
[0259] .sup.1H NMR: DMSO-d.sub.6: .delta. (ppm): 2.1 to 2.7: up:
8H; 2.9: bs: 3H; 3.6 to 4.2: up+2s: 11H; 6.7: up: 4H; 7.1:t:1H;
7.3: td: 1H; 7.4: dd: 1H; 7.8: d: 1H; 7.9: d+up:2H.
[0260] the more polar, isomer B: compound of Example 2 which is
crystallized from a DCM/iso ether mixture and 0.7 g is obtained,
M.p.=164.degree. C.
[0261] .alpha..sub.D.sup.25=-204.degree. (c=0.1; chloroform).
[0262] .sup.1H NMR: DMSO-d.sub.6: .delta. (ppm): 2.5: bs: 6H; 3.1
to 3.7: up+s: 10H; 3.7 to 4.0: 2s: 6H; 6.5 to 6.8: 2up: 3H; 6.9: d:
1H; 7.1: t: 1H; 7.3: t: 1H; 7.5:dd: 1H; 7.8: d: 1H; 7.9: d: 1H;
8.1: bs: 1H.
EXAMPLE 3
[0263]
(3S)-4-[6-Chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphe-
nyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylmorpholine-3-ca-
rboxamide, levorotatory isomer.
[0264] (I): R.sub.1=CH.sub.3; R.sub.2=6-Cl; R.sub.3=OCH.sub.3;
R.sub.4=H; R.sub.5=--N(CH.sub.3).sub.2; R.sub.6=2-OCH.sub.3;
R.sub.7=OCH.sub.3.
[0265] A mixture of 0.61 g of the compound obtained in Preparation
3.3 (isomer B) in 5 ml of DMF is cooled to 4.degree. C. under a
nitrogen atmosphere, 0.06 g of 60% sodium hydride in oil is added
and the mixture is left stirring for 30 minutes at AT. 0.36 g of
2,4-dimethoxybenzenesulf- onyl chloride is then added and the
mixture is left stirring for 2 hours at AT. 50 ml of water are
added to the reaction mixture, it is extracted with AcOEt, the
organic phase is washed with an aqueous 5% Na.sub.2CO.sub.3
solution, with a saturated NaCl solution, dried over
Na.sub.2SO.sub.4 and the solvent is evaporated under vacuum. The
residue is chromatographed on silica gel, elution being carried out
with a DCM/AcOEt (70/30; v/v) mixture. 0.33 g of the expected
product is obtained after crystallization from a DCM/iso ether
mixture, M.p.=159.degree. C.
[0266] .alpha..sub.D.sup.25=-226.degree. (c=0.1; chloroform).
[0267] .sup.1H NMR: DMSO-d.sub.6: .delta. (ppm): 2.0: s: 3H; 2.1 to
2.9: up: 11H; 3.6 to 4.0: up: 11H; 6.6:mt: 3H; 6.9:t: 1H; 7.1:t:
1H; 7.9 to 8.0: mt: 3H
EXAMPLE 4
[0268]
(3S)-4-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulfonyl]-3-(2-methoxyphe-
nyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylmorpholine-3-ca-
rboxamide, levorotatory isomer.
[0269] (I): R.sub.1=Cl; R.sub.2=6-CH.sub.3; R.sub.3=OCH.sub.3;
R.sub.4=H; R.sub.5=--N(CH.sub.3).sub.2; R.sub.6=2-OCH.sub.3;
R.sub.7=OCH.sub.3.
[0270] A mixture of 0.875 g of the compound obtained in Preparation
3.5 (isomer B) in 8 ml of DMF is cooled to 0.degree. C. under an
argon atmosphere, 0.09 g of 60% sodium hydride in oil is added and
the mixture is left stirring until the gaseous emission ceases.
0.49 g of 2,4-dimethoxybenzenesulfonyl chloride is then added and
the mixture is left stirring for 3 hours at AT. The reaction
mixture is poured into water, extracted with AcOEt, the organic
phase is washed with water, with a saturated NaCl solution, dried
over Na.sub.2SO.sub.4 and the solvent is evaporated under vacuum.
The residue is chromatographed on silica gel, elution being carried
out with a DCM/MeOH (97/3; v/v) mixture. 1.02 g of the expected
product are obtained after crystallization from a DCM/iso ether
mixture, M.p.=215-219.degree. C.
[0271] .alpha..sub.D.sup.25=-143.4.degree. (c=0.11;
chloroform).
* * * * *